Macrocyclic compounds useful as inhibitors of histone deacetylases

1. A compound of Formula (I)

wherein

A is aryl or heteroaryl, optionally substituted with one or more groups selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OR 20 , —NR 20 R 22 , —NCOR 20 R 22 and —CONR 20 R 22 ;

Z is —(CH 2 ) n SR 12 ;

R 1 and R 2 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, or R 1 and R 2 together, or one of the R 1 and R 2 together with R 9 form a C 3 -C 10 cycloalkyl or C 3 -C 10 heterocycloalkyl, wherein the C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl and C 3 -C 10 heterocycloalkyl are optionally substituted with one or more groups selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OR 20 , —NR 20 R 22 , —NCOR 20 R 22 and —CONR 20 R 22 ;

R 3 and R 4 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, or R 3 and R 4 together, or one of the R 3 and R 4 together with R 10 form a C 3 -C 10 cycloalkyl or C 3 -C 10 heterocycloalkyl, wherein the C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl and C 3 -C 10 heterocycloalkyl are optionally substituted with one or more groups selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OR 20 , —NR 20 R 22 , —NCOR 20 R 22 , —CONR 20 R 22 and —S(O) m R 20 ;

R 5 and R 6 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, or R 5 and R 6 together, or one of the R 5 and R 6 together with R 11 form a C 3 -C 10 cycloalkyl or C 3 -C 10 heterocycloalkyl, wherein the C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl and C 3 -C 10 heterocycloalkyl are optionally substituted with one or more groups selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OR 20 , —NR 20 R 22 , —NCOR 20 R 22 and —CONR 20 R 22 ;

R 7 and R 8 are independently H, F, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, or R 7 and R 8 together form a C 3 -C 10 cycloalkyl or C 3 -C 10 heterocycloalkyl, wherein the C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl and C 3 -C 10 heterocycloalkyl are optionally substituted with one or more groups selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OR 20 , —NR 20 R 22 , —NCOR 20 R 22 and —CONR 20 R 22 ;

R 9 is independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, or together with one of R 1 and R 2 form a C 3 -C 10 cycloalkyl or C 3 -C 10 heterocycloalkyl, wherein the C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl and C 3 -C 10 heterocycloalkyl are optionally substituted with one or more groups selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OR 20 , —NR 20 R 22 , —NCOR 20 R 22 and —CONR 20 R 22 ;

R 10 is independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, or together with one of R 3 and R 4 form a C 3 -C 10 cycloalkyl or C 3 -C 10 heterocycloalkyl, wherein the C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl and C 3 -C 10 heterocycloalkyl are optionally substituted with one or more groups selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OR 20 , —NR 20 R 22 , —NCOR 20 R 22 and —CONR 20 R 22 ;

R 11 is independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, or together with one of R 5 and R 6 form a C 3 -C 8 cycloalkyl or C 3 -C 8 heterocycloalkyl, wherein the C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl and C 3 -C 10 heterocycloalkyl are optionally substituted with one or more groups selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OR 20 , —NR 20 R 22 , —NCOR 20 R 22 and —CONR 20 R 22 ;

R 12 is independently H, C 1 -C 10 alkyl, —COR 20 , —CONR 20 R 22 , —COOR 20 , —COCR 20 R 22 NR 20 R 22 , —SR 20 , amino acid or —P(O)(OR 24 ) 2 ;

R 20 and R 22 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl or heteroaryl;

R 24 is independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, Na, K or Ca;

m=1 or 2; and

n=1-6;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein A is a 5-membered heteroaryl ring having at least one nitrogen atom.

3. The compound according to claim 1 , wherein A is a 6-membered heteroaryl ring having at least one nitrogen atom.

4. The compound according to claim 2 , represented by Formula (II)

wherein

R 1 -R 12 , R 20 , R 22 , R 24 , Z, m and n are as defined in claim 1 ;

L and Q are independently S, O, N, or CR 26 ; and

R 26 is independently H, halo, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, or heteroaryl, wherein the C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OR 20 , —NR 20 R 22 , —NCOR 20 R 22 , and —CONR 20 R 22 ;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 2 , wherein A is an oxazole or thiazole.

6. The compound according to claim 2 , wherein

R 1 and R 2 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, or R 1 and R 2 together form C 3 -C 10 cycloalkyl;

R 3 and R 4 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, or R 3 and R 4 together form C 3 -C 10 cycloalkyl;

R 5 and R 6 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, or R 5 and R 6 together form C 3 -C 10 cycloalkyl;

R 7 and R 8 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, or R 5 and R 6 together form C 3 -C 10 cycloalkyl;

R 9 , R 10 and R 11 are independently H or C 1 -C 10 alkyl; and

R 12 is —COR 20 , wherein R 20 is independently H or C 1 -C 10 alkyl.

7. The compound according to claim 1 , selected from the group consisting of:

S-(E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-enyl octanethioate;

S-(E)-4-((7S,10S)-7-isopropyl-4,4-dimethyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-enyl ethanethioate;

S-(E)-4-((7S,10S)-7-isopropyl-2,5,8,12-tetraoxo-9-oxa-16-thia-3,6,13,18-tetraazaspiro[bicyclo[13.2.1]octadeca-1[(17),15(18)]diene-4,1′-cyclopropan]-10-yl)but-3-enyl octanethioate; and

S-(E)-4-((7S,10S)-4,4,7-trimethyl-2,5,8,12-tetraoxo-9,16-dioxa-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-enyl octanethioate;

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 3 , represented by Formula (III)

wherein

R 1 -R 12 , R 20 , R 22 , R 24 , Z, m and n are as defined in claim 1 ;

L, Q and Y are independently N or CR 26 ; and

R 26 is independently H, halo, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, or heteroaryl, wherein the C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, —CN, —COOH, —CF 3 , —OCH 2 F, —OR 20 , —NR 20 R 22 , —NCOR 20 R 22 , and —CONR 20 R 22 ;

or a pharmaceutically acceptable salt thereof.

9. The compound of according to claim 8 , wherein

R 1 and R 2 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, or R 1 and R 2 together form a C 3 -C 10 cycloalkyl;

R 3 and R 4 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, or R 3 and R 4 together form a C 3 -C 10 cycloalkyl;

R 5 and R 6 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, or R 5 and R 6 together form a C 3 -C 10 cycloalkyl;

R 7 and R 8 are independently H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, or R 7 and R 8 together form a C 3 -C 10 cycloalkyl;

R 9 , R 10 and R 11 are independently H or C 1 -C 10 alkyl; and

R 12 is —COR 20 , wherein R 20 is independently H or C 1 -C 10 alkyl.

10. The compound according to claim 1 , which is

(7S,10S)-4,4-dimethyl-10-[(1E)-4-(octanoylsulfanyl)but-1-en-1-yl]-7-(propan-2-yl)-9-oxa-3,6,13,19-tetraazabicyclo[13.3.1]nonadeca-1(18),15(19),16-triene-2,5,8,12-tetrone;

or a pharmaceutically acceptable salt thereof.

11. A compound of Formula (IV):

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 1 , further comprising one or more anti-cancer agents.